Alzheimer's disease (AD) is a common dementia or loss of cognitive abilities, which is linked to degeneration of brain tissue. While the cause of this neurodegeneration remains to be proven, several possible mechanisms are being studied, as a first step towards designing therapies for this debilitating and costly disease of the elderly. Early events involved the intracellular of Abeta peptides could lead to neuronal alterations and cellular death, while later increased extracellular Abeta deposits could initiate a secondary phase of inflammatory events that could accelerate local neuronal damage, loss, and decline of cognitive function. If this hypothesis is basically correct, it provides specific targets for therapeutic interventions, such as enhancing clearance of Abeta, facilitating the degradation of Abeta, inhibiting of complement activation by Abeta, and inhibiting inflammatory events evoked by both the activation of C' by Abeta fibrils and by Abeta interaction(s) with microglia to trigger generation of neurotoxic products. It has been proposed that generation of antibodies to the Abeta peptide would enhance the clearance of Abeta in AD patients or patients at risk for AD. This proposal will test the hypothesis that antibody alone or antibody and complement will have a neuroprotective effect when the amount of Abeta added is low and/or is not in fibrillar conformation, but that as the Abeta load increases, increased complement activation by extracellular Abeta deposits/plaques will induce increased pro-inflammatory activity resulting in neurotoxicity. It is critical to determine these effects prior to human clinical trials of the immunization strategy. This proposal will utilize the unique availability of sufficient quantities of essential and custom reagents provided in the Tissue and Peptide Resource Core of this Program Project, to test specific hypotheses concerning the factors regulating uptake of Abeta, the consequences of cellular interactions mediating Abeta ingestion, and the potential requirement for stage specific therapeutics Abeta-containing immune complex, the observations will shed light on the differential processing of proteins as a function of the path of entry to the cell and of molecular complex that is engulfed. In addition, since antibody and antibody-induced complement activation have been implicated in a number of other neurodegenerative disorders, it is likely that some of our findings will be relevant to other diseases as well. Finally, these studies will result in the development of novel relevant animal models for testing potential therapies for a number of diseases in an vivo context.